Overall Abstract The Center for Solutions for ME/CFS (CfS for ME/CFS) is an inter-disciplinary, inter-institutional center comprised of clinicians, clinical investigators, basic scientists who are committing to working together to understand the pathogenesis of ME/CFS and develop evidence-based strategies for interventions that prevent and mitigate disease. The team initially coalesced with an NIH call to respond to spurious reports linking xenotropic murine leukemia virus-related virus (XMRV) to ME/CFS. It consolidated its vision with support from the Hutchins Family Foundation Chronic Fatigue Initiative (CFI) and a crowd-funding organization, The Microbe Discovery Project, to explore the role of infection and immunity in disease and identify biomarkers for diagnosis through functional genomic, proteomic, and metabolomic discovery. The foundation for this project is a large clinical database and sample repository representing oral, fecal, and blood samples from well-characterized ME/CFS subjects and frequency-matched controls collected nationwide over a period of several years. In Project 1, we survey for the presence of molecular footprints of bacterial, fungal, and viral agents and corresponding immune responses in a 100 case/100 control subset of repository samples using high throughput sequencing, high density peptide arrays, and immune signature assays; this Project also examines the prevalence of autoantibodies selected based on clinical and literature reports. In Project 2, we profile the plasma metabolome and PBMC transcriptome in the same subjects studied in Project 1 using state-of-the-art mass spectrometric and RNA-seq methods, comprehensive mass spectral libraries, and tools for RNA profiling in bulk cell populations using cell sub-type specific markers. We also pursue metabolomic and transcriptomic analyses after orthostatic and exercise challenges using samples collected in Project 3. In Project 3, we mine existing databases at Columbia and the CFI for insights into clinical features, comorbidities, and sub-types that can be used to refine laboratory analyses, as well as enhance patient care. We will work with clinicians and the ME/CFS community to design a mobile app that will allow patients and caregivers to track clinical status in response to stressors and interventions, and will provide prospective research data. We will also investigate the utility of the Lean Test as a simple outpatient test for autonomic function.